Grow Taller with Growth Hormone Receptor

Previously, it has been reported that herbal treatments to increase growth hormone levels may be effective in terms of helping you to grow taller based on growth hormone sensitivity.  Growth Hormone sensitivity is based off the Growth Hormone Receptor.  How effective HGH is in terms of increasing height is all based on how HGH interacts with HGHR.  How do we alter our growth hormone receptors in such a way as to grow taller?  Are there any chemical or mechanical means of altering the GH receptors? 

Nutrition-induced catch-up growth at the growth plate. 

"The effect of 40% food restriction (FR) and replenishment on the growth hormone (GH) and insulin-like growth factor-I (IGF-I) axis in the epiphyseal growth plate (EGP) was examined in a mouse model. Changes in RNA and protein levels were evaluated with real time PCR and immunohistochemistry, respectively, and serum levels of IGF-I and leptin were measured with radioimmunoassay. Dramatic changes in weight, tibial length and EGP height were observed following 10 days of 40% FR. The protein levels of IGF-I receptor (IGF-IR) and GH receptor (GHR), which were reduced during FR, increased during catch-up growth without an apparent change in the level of their RNA. The levels of type II and X collagens were unchanged. Serum IGF-I and leptin levels were reduced during FR and increased during catch-up growth. Following 40% FR, there was a significant decrease in the level of GHR and IGF-IR in the EGP which may explain the reduced effect of GH treatment in malnourished animals and children." 

Fasting reduces the levels of Growth Hormone Receptors.  Growth Hormone Receptors affect the ability of Growth Hormone to increase height and it may explain why Growth Hormone treatment usually only works in growth hormone deficient individuals as growth hormone only works per the number of GHR already exists. 

Vitamin D and growth hormone regulate growth hormone/insulin-like growth factor (GH-IGF) axis gene expression in human fetal epiphyseal chondrocytes. 

"Cell proliferation and gene expression regulation were studied in human fetal epiphyseal chondrocytes to ascertain the involvement of GH-IGF axis components in human fetal growth regulation by 1,25-dihydroxyvitamin D(3) (VitD)[This is the active form of Vitamin D; the one activated by sunlight] and growth hormone (GH).
Chondrocytes from primary cultures were plated in serum-free medium for 48 h and incubated for a further 48 h with VitD (10(-11) to 10(-6)M) and/or IGF-I (100 ng/ml) and/or GH (500 ng/ml). We analyzed (3)H-thymidine incorporation into DNA and IGF-I, IGFBP-3, GHR, SOX9, COL2A1, aggrecan and COMP gene expression by real-time quantitative PCR.
VitD dose-dependently and significantly inhibited (3)H-thymidine incorporation whereas GH had no effect on proliferation and, when combined with VitD, the same inhibition was observed as with VitD alone. IGF-I (100 ng/ml) significantly stimulated proliferation and opposed inhibition by VitD. VitD dose-dependently stimulated IGF-I (11.1+/-19.8 at VitD10(-6)M), IGFBP-3 (2.6+/-0.9), GHR (3.8+/-2.8) and COMP (1.5+/-0.6) expression whereas it inhibited SOX9 (0.7+/-0.2), COL2A1 (0.6+/-0.3) and aggrecan (0.6+/-0.2) expression and had no significant effect on IGF-II[Vitamin D increases Growth Hormone Receptor effectiveness]. IGF-I stimulated IGF-I, IGFBP-3, SOX9, COL2A1 and aggrecan expression and opposed COL2A1 and aggrecan gene expression inhibition by VitD. GH alone had no effect on gene expression whereas, in the presence of VitD, significantly-increased IGF-I expression stimulation was observed above values obtained with VitD alone (17.5+/-7.4).
Our results suggest that VitD regulation of fetal growth cartilage could have consisted of parallel enhancing of cell differentiation and conditioning to a phenotype more sensitive to regulation by other hormones such as GH as shown by increased GHR and IGF-I expression, but not by IGF-II expression which was not regulated."

Vitamin D is one of those hormones where a proper balance is needed where too much active Vitamin D(by transgenic Cyp27b1) inhibits growth and too little active Vitamin D also inhibits growth.   This effect could be based on Vitamin D Receptors which inhibit celullar proliferation.  Vitamin D levels are beneficial for only as many as you have receptors and excess Vitamin D above and beyond the number of receptors you have may be damaging.

Vitamin D does increase growth hormone receptors however.  Unfortunately it is not known how to best optimize the beneficial effects of Vitamin D so we can't count on it to increase GHR levels for now. 

Spatial distribution of growth hormone receptor, insulin-like growth factor-I receptor and apoptotic chondrocytes during growth plate development. 

"To investigate the contribution of GH, IGF-I and apoptosis to growth plate function, the expression of GH receptor (GHR) and IGF-I receptor (IGF-IR) mRNA were evaluated by in situ hybridization in fractionated costochondral growth plates of growing rats (at 2, 4, and 7 weeks). Apoptosis was determined by TUNEL assay and morphology in histological sections. GHR mRNA was greatest in resting cells with hypertropic cells increasing GHR expression with increasing age. Hypertropic and resting cell IGF-IR mRNA declined over the ages studied. Receptor mRNA expression was altered by exposing cells to GH or IGF-I. GH and IGF significantly decreased GHR mRNA in proliferative cells. GH and IGF also decreased IGF-IR mRNA in resting cells and the 2- and 4-week-old proliferative and hypertropic cells. Treating cells in culture with GH increased the number of apoptotic cells across all ages and zones. Histologically, apoptotic cells were observed at the chondro-osseous junction and within actively proliferating chondrocytes but not in resting cells. Apoptosis was highest at 4 weeks of age with lateral regions displaying the greatest number of cells undergoing apoptosis. These data indicate that apoptosis plays a role in growth plate function, particularly spatial configuration as indicated by the preferential lateral cell apoptosis. The susceptibility of proliferative cells to GHR and IGF-IR down regulation during the period of greatest apoptosis supports a role for the GH-IGF axis in both proliferation and apoptosis during growth plate development." 

GHR expression changes as the organism ages.  It would be extremely difficult for a mechanical or chemical method to preferentially increase GHR in proliferative chondrocytes but not hypertrophic chondrocytes.  Thus maybe modulating GHR isn't the best way to achieve height increase. IGF-1R universally decreases with age so perhaps it would be best to try to increase those levels. 

"While the terminal, juxtametaphyseal apoptotic chondrocytes were retracted from their lacunae, presumably due to the mineralized inter-territorial cartilage matrix, the condensed apoptotic cells located outside of the ossification front were tightly surrounded by matrix. It is logical that the pericellular matrix would remain in contact with an apoptotic cell in the proliferative and non-terminal hypertropic zones because the growth plate, in general, is a well-hydrated, flexible substrate. When an apoptotic cell condenses it would lose water to its immediate surroundings, thereby increasing the hydration of the pericellular matrix making that extracellular matrix likely to follow the shrinking cell. As demonstrated by this work, non-terminal hypertropic cells and chondrocytes of the proliferative zone can also be removed by programmed cell death, although not likely for the same reason as terminal cells that must become apoptotic to permit the process of osteogenesis."  

So cells other than terminal cells must undergo apoptosis to help organize the extracellular matrix. Growth Hormone increased the number of apoptotic cells but that could be due to the growth plate needing more apoptotic cells to organize the growth plate rather than growth hormone causing apoptosis. 

Localization and regulation of the growth hormone receptor and growth hormone-binding protein in the rat growth plate. 

"Growth hormone (GH) has direct effects on the growth plate to stimulate longitudinal growth. The dual effector theory suggests that GH would act primarily on the "stem cells"[acting on the stem cells is more likely to induce greater adult height over growth rate than other growth plate cell types] However, staining with a GH receptor (GHR) antibody is found in all layers of the growth plate in rabbits and humans. We now have investigated the localization and regulation of GHR and the related GH binding protein (GHBP) in the rat growth plate using a sensitive immunohistochemical method involving tyramide signal amplification (TSA) and antibodies specific for GHR or GHBP. Both GHR and GHBP were shown in the germinal and proliferative chondrocytes, but most clearly in early maturing chondrocytes at the interface between proliferative and hypertrophic cells. Staining for GHR and GHBP was located in both the cytoplasm and the nucleus. Expression of GHR mRNA and GHBP mRNA in the growth plate was confirmed by reverse-transcription polymerase chain reaction (RT-PCR). Immunohistochemical staining for GHR and GHBP decreased with age; in 12-week-old normal rats, only the early maturing chondrocytes were stained. In GH-deficient dwarf rats, staining seemed less than in normal rats, and in hypophysectomized (Hx) rats, staining for GHBP was clearly reduced. Treatment of Hx rats with thyroid hormones (T3 + T4), via subcutaneously (sc) implanted osmotic minipumps, induced little growth and induced a small layer of GHR-positive and GHBP-positive early maturing chondrocytes. Treatment with GH and thyroid hormones (TH) resulted in greater growth and a broader layer of GHR-positive and GHBP-positive cells, indistinguishable from normal rats. In contrast, dexamethasone treatment of normal rats inhibited their growth and reduced GHR and GHBP staining in the growth plate. These results show that GHR and GHBP in the growth plate are under hormonal control. The localization of GHR/GHBP suggests that in addition to actions on germinal and proliferative cells in young rats, GH also has effects on early maturing chondrocytes and may be involved in their differentiation to a fully hypertrophic chondrocyte." 

So Thyroid Hormone and Growth Hormone itself may increase GHR and GHBP levels meaning that methods of increasing GH levels may be an effective means of increasing height.  This may be limited however and GH and TH may only increase GHR and GHBP up to a certain point.  As can be seen in the previous study where GH began to reduce GHR. 

"There also is direct evidence that GH acts on the stem cells resulting in differentiation to a proliferative cell type that produces IGF-I, which then acts in an autocrine or paracrine fashion to induce further proliferation and clonal expansion of the chondrocytes."<-So IGF-1 may be a side effect of chondrogenic differentiation where GH is the cause.

"T3/T4 treatment alone induced a small row of positive cells(GHBP) in the transition zone between the proliferative and hypertrophic zone"<-This row of GHBP may be important for height growth which means thyroid hormones are important for height growth.

"GHBP staining was clearly reduced in proliferative chondrocytes of the dexamethasone-treated rats and was hardly detectable in the rats treated with the highest dose"<-Dexamethasone reduces length and Dexamethasone reduces GHBP therefore it's possible(logical fallacy aside) that GHBP increases length.

"We found that dexamethasone acts as a negative regulator of GHR/GHBP in the growth plate. Staining for GHR and GHBP had almost disappeared not only from resting zone cells and proliferative chondrocytes but also from early maturing chondrocytes. This agrees with earlier results on dexamethasone suppression of GHR expression"<-another study found however that dexamethasone upregulated GHR.

So we are back to the point where Growth Hormone only works for as many growth hormone receptors you have(people with gigantism likely have transgenic levels of GHR).  The active metabolite of Vitamin D seems to increase GHR levels.  It seems that sunlight is definitely good for babies at least...  The active metabolite of vitamin D may accelerate terminal differentiation during later stages of development as more GHR is in the hypertrophic cells.